NK cell activation provides protection against herpes simplex encephalitis through TLR3/TRIF-dependent crosstalk between epithelial and dendritic cells

Herpes simplex encephalitis (HSE), which is a fatal disease causing focal or global cerebral dysfunction following infection with herpes simplex virus type 1 (HSV-1). Previous few studies have been administered on the immunopathological networks of HSE in the context of TLR3 and TRIF defects at the cellular and molecular levels. In this work, we tried to decipher the crosstalk between type I IFN (IFN-I)-producing epithelial layer and IL-15-producing dendritic cells (DC) to activate NK cells for the protective role of TLR3/TRIF pathway in HSE progression after vaginal HSV-1 infection. TLR3- and TRIF-knockout mice showed enhanced susceptibility to HSE progression, with high HSV-1 burden in vaginal tract, lymphoid system, and CNS. The increased HSV-1 burden in TLR3- and TRIF-ablated mice did not correlate with increased infiltration of Ly-6C +monocytes, but it was closely associated with impaired NK cell activation in vaginal tract. In addition, using delicate ex vivo experiments and bone marrow transplantation, TRIF deficiency in tissue-resident cells, such as epithelial cells in vaginal tract, found to cause impaired NK cell activation by means of low IFN-I production, whereas IFN-I receptor in DC play a role in activating NK cells via IL-15 production in response to IFN-I produced from epithelial layer. These results provide new information about IFN-I- and IL-15-mediated crosstalk between epithelial cells and DC at the primary infection site that can suppress HSE progression in a TLR3- and TRIF-dependent manner. This study was supported by the Basic Science Research Program through National Research Foundation of Korea (NRF) grants funded by the Ministry of Education and the Ministry of Science and ICT (MSIT), Republic of Korea (2021R1A2B5B02001578, 2019R1A6A1A03033084 for Seong Kug Eo, 2020R1I1A1A01054533 for Erdenebileg Uyangaa, and 2020R1I1A2055591 for Jin Young Choi, http://www.nrf.re.kr).